1. Field of the Invention
The present invention relates to novel 4,5-dihydro-1H-2,4-aryl fused diazepines, and benzodiazocines to related diamines and aminoamides, to processes for preparing them and to methods and compositions for treating cardiac arrhythmias in mammals utilizing said 4,5-dihydro-1H-2,4-benzodiazepines, and diazocines.
2. Information Disclosure Statement
U.S. Pat. No. 3,696,093 to Rodriguez et al. discloses a single 3,4-disubstituted benzodiazepine: 3,4-dimethyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride. ##STR3## Also disclosed are 4,5-dihydro-1H-2,4-benzodiazepines monosubstituted in the 3 position with benzyl, dimethylaminoethyl, amino, 1-piperidinylmethyl, and phenyl. The compounds are said to be useful as cardiovascular agents, for example, in the treatment or management of the various forms of hypertension or of congestive heart failure. The patent does not disclose antiarrhythmic properties for the genus, and the single example of a disubstituted benzodiazepine was found to be inactive as an antiarrhythmic when tested in the protocol used to evaluate the compounds of the present invention.
Japanese application 59/013766 (CA 101:23612m) discloses a series of 1,2,4-trisubstituted-tetrahydrobenzodiazepines of general structure ##STR4## wherein R.sup.1 is lower alkyl or phenethyl (opt. substd. with lower alkoxy). The compounds are said to be analgesics.
Elslager et al [J. Het. Chem. 5, 609-613 (1968)] describe the synthesis of a series of tetrahydrothiazolo-[3,2-b][2,4]benzodiazepines. The authors state that "None of the compounds possessed appreciable biological activity." As intermediates in the synthesis, they disclose ##STR5## 1,2,4,5-tetrahydro-3H-2,4-benzodiazepine-3-thione and 2,5,dihydro-3-(methylthio)-1H-2,4-benzodiazepine hydroiodide.
U.S. Pat. No. 4,840,948 to Lang et al. discloses a series of 1-(hydroxystyryl)-5H-2,3-benzodiazepines of general formula: ##STR6## wherein R stands for a hydrogen or halogen atom, or a C.sub.1-4 alkoxy group,
R.sup.1 represents a hydrogen atom or a C.sub.1-4 alkyl group, PA1 R.sup.2 and R.sup.3 are identical and denote a C.sub.1-4 alkyl group, PA1 or combined they denote a methylene group. PA1 R.sub.2 represents hydrogen, lower alkyl or lower alkenyl, PA1 R.sub.3 represents a group of the formula a, b, c, or d ##STR12## wherein R is hydrogen or C.sub.1 -C.sub.3 -alkyl, R.sub.4 is hydrogen, lower alkyl, lower alkoxy, nitro or halogen, in particular chlorine or bromine, and R.sub.4 ' is hydrogen or C.sub.1 -C.sub.4 -alkyl, and the aromatic groups A and B independently from each other each may be unsubstituted or be substituted by 1 to 3 substituents selected from the group consisting of halogen, lower alkythio, lower alkoxy, lower alkyl, hydroxy, nitro and trifluoromethyl, or be substituted at two adjacent carbon atoms by methylenedioxy or ethylenedioxy, and optical isomers and pharmaceutically-acceptable acid addition salts thereof. The compounds are said to exhibit pscho pharmacological, diuretic, antiarrhythmic and analgesic activities. A substantially similar disclosure can be found in Zeugner et al., U.S. Pat. No. 4,382,030, issued May 3, 1983, which is a divisional of U.S. Pat. No. 4,325,957. PA1 R.sup.1 is hydrogen, lower-alkyl, benzyl, naphthyl, thienyl, pyridinyl, phenyl, or phenyl having one or two substituents chosen from the group consisting of lower-alkyl and lower-alkoxy; PA1 R.sup.2 is hydrogen; lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-alkyl or lower-alkoxy; or PA1 R.sup.2 is --CH.sub.2 CH.sub.2 R.sup.7 where R.sup.7 is lower-alkoxy; benzyl; di-(lower-alkyl)amino, pyrrolidino; piperidino; morpholino; pyridinyl; phenyl; or phenyl substituted with amino, nitro or lower-alkylsulfonamido; PA1 R.sup.3 is Y.sub.p --(CH.sub.2).sub.m --X.sub.n --R.sup.8 wherein PA1 Y is --NH--, --O--, --S--, or ##STR14## p is zero or one; m is an integer from zero to seven; ##STR15## n is zero or one; and R.sup.8 is hydrogen; lower-alkyl; phenyl; furanyl; thienyl; pyridinyl; phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl, nitro, hydroxy, lower-alkoxy, lower-alkylamido, lower-alkylsulfonamido polyfluorolower-alkylsulfonamido, lower-alkylaminosulfonyl, dilower-alkylaminosulfonyl, and amino; or when n is zero and m is other than zero, R.sup.8 is additionally halogen; benzyl(lower-alkyl)amino; di-(lower-alkyl)amino; or a 5- or 6-membered heterocycle containing one or two nitrogens, said heterocycle being unsubstituted or substituted with one lower-alkyl group; or X and R.sup.8 taken together are cyclohexylidine; PA1 R.sup.4 is hydrogen; lower-alkyl; allyl; lower-alkoxy-lower-alkyl; acetyl; lower-alkylaceto; lower-alkyl carboxyl; or .alpha.-hydroxy-lower-alkyl; and PA1 R.sup.5 is hydrogen; lower-alkyl; naphthyl; thienyl; pyridinyl; benzyl; phenyl; or phenyl having one or two substituents chosen independently from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxyl, amino, di-(lower-alkyl)amino, lower-alkylsulfonamido, lower-acylamino, lower-alkylthio, and lower-alkylsulfonyl; PA1 or an acid-addition salt thereof; PA1 A, R.sup.1, and R.sup.4 are as defined hereinabove and R.sup.2 is hydrogen; lower-alkyl; benzyl; phenyl; phenyl substituted with halogen, lower-alkyl or lower-alkoxy; or PA1 R.sup.2 is --CH.sub.2 CH.sub.2 R.sup.7 where R.sup.7 is lower-alkoxy; benzyl; di-(lower-alkyl)amino, pyrrolidino; piperidino; morpholino; phenyl; or phenyl substituted with amino, nitro or lower-alkyl sulfonamido; PA1 R.sup.3 is Y.sub.p --(CH.sub.2).sub.m --X.sub.n --R.sup.8 wherein PA1 Y is --NH--, --O--, --S--, or ##STR16## p is zero or one; m is an integer from zero to seven; ##STR17## n is zero or one; and R.sup.8 is hydrogen; lower-alkyl; phenyl; furanyl; thienyl; pyridinyl; phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl, nitro, hydroxy, lower-alkoxy, lower-alkylamido, lower-alkylsulfonamido dilower-alkylaminosulfonyl, and amino; or when n is zero and m is other than zero, R.sup.8 is additionally halogen; benzyl(lower-alkyl)amino; di-(lower-alkyl)amino; or a 5- or 6-membered heterocycle containing one or two nitrogens, said heterocycle being unsubstituted or substituted with one lower-alkyl group; or X and R.sup.8 taken together are cyclohexylidine; and PA1 R.sup.5 is hydrogen; lower-alkyl; naphthyl; thienyl; pyridinyl; benzyl; phenyl; or phenyl having one or two substituents chosen independently from the group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxyl, amino, di-(lower-alkyl)amino, lower-alkylsulfonamido, and lower-acylamino; PA1 or an acid-addition salt thereof; PA1 R.sup.5b is hydrogen; lower-alkyl; phenyl; phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy, and halogen; naphthyl; thienyl; pyridinyl; or benzyl; PA1 R.sup.6 is one or two substituents chosen independently from the group consisting of hydrogen, lower-alkyl, lower-alkoxy, halogen, nitro, and lower-alkylsulfonamido; or R.sup.6 is a fused benzene ring; PA1 R.sup.15 is hydrogen or, when R.sup.1 is phenyl, R.sup.15 may additionally be lower-alkyl; PA1 R.sup.16 is (CH.sub.2).sub.m --(X.sup.a).sub.n --R.sup.8a ; PA1 q is one or two; or an acid addition salt thereof. PA1 R.sup.5d is lower-alkyl; phenyl; naphthyl; thienyl; pyridinyl; benzyl; or phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy and halogen; PA1 R.sup.6a is one or two substituents chosen independently from the group consisting of hydrogen, lower-alkyl, lower-alkoxy and halogen; or an acid-addition salt thereof. PA1 R.sup.5a is hydrogen; phenyl; phenyl having one or two substituents chosen from the group consisting of halogen, lower-alkyl and lower-alkoxy; naphthyl; thienyl; pyridinyl; or benzyl; PA1 R.sup.9 is hydrogen, lower-alkyl, benzyl, phenethyl or [di-(lower-alkyl)amino]lower-alkyl; PA1 R.sup.10 is hydrogen; lower-alkyl; phenyl; phenyl substituted with halogen, lower-alkyl, lower-alkylsulfonamido or lower-alkoxy; phenoxy; phenoxy substituted with halogen, lower-alkyl or lower-alkoxy; benzyl; or R.sup.10 is a 5- or 6-membered heterocycle containing one or two nitrogens; and PA1 R.sup.2a is --CH.sub.2 CH.sub.2 R.sup.7 where R.sup.7 is lower-alkoxy, phenyl, benzyl, di-(lower-alkyl)amino, pyrrolidino, piperidino, or morpholino; and PA1 Y.sup.a is --O--, --S-- or ##STR24## and X.sup.a is --S--, --SO.sub.2 --, --O-- or --CH.dbd.CH--; PA1 R.sup.5c is phenyl; phenyl having one or two substituents chosen from the group consisting of lower-alkyl, lower-alkoxy and halogen; naphthyl; thienyl; or pyridinyl; PA1 R.sup.1 is hydrogen or phenyl; PA1 R.sup.2 is lower-alkyl or --CH.sub.2 CH.sub.2 R.sup.7' wherein R.sup.7' is lower-alkoxy, pyridinyl, phenyl or phenyl having one or two lower-alkylsulfonamido substituents; PA1 R.sup.3 is --(CH.sub.2).sub.m --X.sub.n --R.sup.8 wherein PA1 m is an integer from zero to seven; PA1 X.sub.n is --S--, --O--, --SO.sub.2 --, --CH.dbd.CH--, or --NHSO.sub.2 --; PA1 n is zero or one; PA1 R.sup.8 is lower-alkyl, phenyl, pyridinyl, phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkylsulfonamido, dilower-alkylaminosulfonyl and polyfluoro-lower-alkylsulfonamido; or pyridinyl having one or two lower-alkyl substituents; PA1 R.sup.4 is hydrogen or lower-alkyl; and PA1 R.sup.5 is hydrogen, pyridinyl, benzyl, phenyl or phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkylsulfonyl, lower-alkylsulfonamido, and hydroxy; PA1 or an acid-addition salt thereof; with the proviso that the total number of carbon atoms in R.sup.1 plus R.sup.2 plus R.sup.4 plus R.sup.5 must be five or greater; further provided that at least one of R.sup.2, R.sup.3, R.sup.5 or ring A must contain a pyridinyl group, an --NHSO.sub.2 -- group, or a lower-alkylsulfonamido, dilower-alkylaminosulfonyl, or polyfluorolower-alkylsulfonamido substituent. PA1 R.sup.1 is hydrogen or phenyl; PA1 R.sup.2 is lower-alkyl or --CH.sub.2 CH.sub.2 R.sup.7' wherein R.sup.7' is lower-alkoxy, pyridinyl, phenyl or phenyl having one or two lower-alkylsulfonamido substituents; PA1 R.sup.3 is --(CH.sub.2).sub.m --X.sub.n --R.sup.8 wherein PA1 m is an integer from zero to seven; PA1 X.sub.n is --S--, --O--, --SO.sub.2 --, --CH.dbd.CH--, or --NHSO.sub.2 --; PA1 n is zero or one; PA1 R.sup.8 is lower-alkyl, phenyl, pyridinyl, phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkylsulfonamido, dilower-alkylaminosulfonyl and polyfluoro-lower-alkylsulfonamido; or pyridinyl having one or two lower-alkyl substituents; PA1 R.sup.4 is hydrogen or lower-alkyl; and PA1 R.sup.5 is hydrogen, pyridinyl, benzyl, phenyl or phenyl having one or two substituents chosen independently from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkylthio, lower-alkylsulfonyl, lower-alkylsulfonamido, and hydroxy; PA1 or an acid-addition salt thereof; together with a pharmaceutically acceptable vehicle, adjuvant or excipient; with the proviso that the total number of carbon atoms in R.sup.1 plus R.sup.2 plus R.sup.4 plus R.sup.5 must be five or greater; further provided that at least one of R.sup.2, R.sup.3, R.sup.5 or ring A must contain a pyridinyl group, an --NHSO.sub.2 -- group, or a lower-alkylsulfonamido, dilower-alkylaminosulfonyl, or polyfluorolower-alkylsulfonamido substituent.
The compounds are said to be positive inotropes and therefore useful as cardiotonics.
Carr et al., European Patent Application 389765, published Oct. 30, 1990, disclose compounds of the formula: ##STR7## in which Q is represented by a substituent selected from the group consisting of (CH.sub.2).sub.n in which n is an integer from 2-10, ##STR8## A is a substituent selected from the group consisting of --NH--(CH.sub.2).sub.m in which m is an integer from 0-5, a piperidino substituent, or a piperazino substituent; both Ar and Ar.sub.1 are each independently represented by a phenyl ring each of which may be optionally substituted with up to 3 substituents, each selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, and trifluoromethyl; and R is represented by hydrogen or C.sub.1-4 alkyl; R.sub.1 is represented by hydrogen or C.sub.1-4 alkyl; the optical isomers and tautomers thereof; and the pharmaceutically acceptable acid addition salts thereof; with the provisos that: 1) when Q is represented by (CH.sub.2).sub.2,3 or .sub.4, then A is not represented by NH--(CH.sub.2).sub.o ; and 2) when Q is represented by (CH.sub.2).sub.2 and R is a C.sub.1-4 alkyl; then A is not NH--(CH.sub.2). The compounds are said to be useful as calcium antagonists and thus to be useful in the treatment of a variety of disease states, for example, cardiac arrhythmias, angina, depression, hypertension, epilepsy and mania.
Rodriquez and Stevens, GB 1183135, published Mar. 4, 1970, disclose 4,5-dihydro-1H-2,4-benzodiazepines of the formula: ##STR9## in which Ph represents an optionally substituted 1,2-phenylene group, R.sub.1 and R.sub.4 (which may be the same or different) each represents two hydrogen atoms or two aliphatic groups, or a hydrogen atom together with an aliphatic group, an araliphatic group, an aromatic group, a heterocyclic group of aromatic characteristics or a heterocyclic-aliphatic group, in which the heterocyclic portion has aromatic characteristics; R.sub.2 represents a hydrogen atom, a hydroxy group, a mercapto group, an optionally substituted amino group, an aliphatic group, an araliphatic group, an aromatic group, a heterocyclic group of aromatic characteristics or a heterocyclic-aliphatic group, in which the heterocyclic portion has aromatic characteristics; and R.sub.3 represents a hydrogen atom, an aliphatic group, an araliphatic group, an aromatic group, a heterocyclic group of aromatic characteristics or a heterocyclic-aliphatic group, in which the heterocyclic portion has aromatic characteristics, or the acyl group of a carboxylic acid; N-oxides, quaternary derivatives and salts thereof. The compounds are said to be useful as cardiovascular agents, for example, in the treatment of congestive heart failure; and as coccidiostatic or CNS-stimulating agents. A substantially similar disclosure can be found in Rodriquez and Stevens, DE 11770135, published Sep. 23, 1971.
Zeugner et al., European Patent Application 66303, published Dec. 8, 1982, disclose compounds of the formula: ##STR10## wherein R.sub.1 is H or lower-alkyl; rings A and B have 0-3 substituents selected from halogen, lower-alkylthio, lower-alkoxy, lower-alkyl, OH, NO.sub.2 and CF.sub.3, or a methylenedioxy or ethylenedioxy group attached to 2 adjacent C atoms. The compounds are said to be useful as intermediates and to have sedative, broncholytic and antiarrhythmic activity.
Zeugner et al., U.S. Pat. No. 4,325,957, issued Apr. 20, 1982, disclose compounds of the formula: ##STR11## wherein R.sub.1 represents hydrogen, lower alkyl, lower alkenyl or cyclopropylmethyl,